Integrating 4 methods to evaluate physical function in patients with cancer (In4M): protocol for a prospective cohort study

Introduction Accurate, patient-centred evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterise the longitudinal measurement characteristics of physical function assessments, including clinician-reported outcome, patient-reported ported outcome (PRO), performance outcome tests and wearable data, to inform regulatory and clinical decision-making in cancer clinical trials and oncology practice. Methods and analysis In this prospective study, we are enrolling 200 English-speaking and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centred health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable sensor. Data analysis will focus on understanding variability, sensitivity and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multimodal physical function data collection in real-world patients with breast cancer or lymphoma will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform and PROs. Ethics and dissemination This study has received approval from IRBs at Mayo Clinic, Yale University and the US Food and Drug Administration. Results will be made available to participants, funders, the research community and the public. Trial registration number NCT05214144; Pre-results.


GENERAL COMMENTS
Thanks for the opportunity to review this manuscript titled 'Integrating 4 Measures to Evaluate Physical Function in Patients with Cancer (In4M): Protocol for a prospective study' for publication in BMJ Open.The manuscript outlines the protocol for a study currently recruiting to characterise longitudinal measurement characteristics (variability, sensitivity and meaningful changes) of a range of different physical function tests in people with breast cancer or lymphoma receiving chemotherapy.The study will also report on physical function relationships to clinical outcomes and feasibility of data collection.The manuscript will make an important contribution to scientific knowledge on this topic and I have made only a few suggestions below for the authors to consider in a revised version of the manuscript.
Title -rather than 4 'measures' perhaps the title would be more accurate if it was 4 'approaches' to measure… -given for the PRO approach several measures are being used Introduction Page 11 lines 32-41would be more informative if the strength of the correlations mentioned in this section were presented (e.g., r values or 'fair', 'good' etc as defined by Cohen) Brief background regarding the development of 'Hugo Health' would help the reader to understand how the measurements are truly 'patient-centred'.For example were patients or carers involved in its design?Readers can then refer to the previous publications for additional information.

PerfO
Page 15 line 24the 6MWT is being performed once, yet the guidelines from the ATS/ERS state that 2 tests should be performed to account for any potential learning effects (Holland et al, ERJ, 2014).Changes in performance which are measured between the two timepoints could be a result of learning effects rather than true change in performance and this should be stated as a limitation to the study methods.

Wearable data
Wear of devices for 9 months day and night, with data uploads every 3 days, is asking a lot of participants, particularly when most clinical trials have a 7-10 day wear period at each assessment timepoint and include data so long as 4 days of 8 hours data/day is available.Given data collection is continuous over the 9 months how will missing data be reported (e.g., will it be clear if participants have met minimum data requirements as outlined above)?
Will participants be able to withdraw from this component of the study and continue completing the other assessments if they wish to?
Exit Throughout the manuscript and including the title -the use of patients with cancer is correct but best to be specific to breast cancer and lymphoma patients.
Response: We appreciate this suggestion.We have reviewed the manuscript again and made the appropriate changes to terminology where appropriate and not redundant.
In the methods under Clinro and Perfo, another site was suggested -please elaborate on this.
Similarly in this same sentence, how will not having a 6MWT at this other site effect or impact the comparison in terms of patient recruitment?It seems that the authors have already collected data on this and this protocol looks retrospective rather than prospective.
Response: Thank you for bringing this to our attention.For clarity, we updated the third sentence to "Participants receiving care at a site other than Mayo Clinic Rochester or Yale University sites will not have an additional 6MWT observation." In the In4M study, participants are recruited at Yale, community sites affiliated with Yale, and Mayo Clinic Rochester, and can be treated at a local community site and followed remotely after study consent and enrollment is obtained at the primary Yale or Mayo site (as per the 2nd paragraph of the Methods section).Participants who receive treatment at a site outside of Yale University, a community site affiliated with Yale, or Mayo Clinic Rochester have a 6-minute walk test at baseline, but not in follow up.While it would have been ideal to measure the 6MWT longitudinally in patients at all sites, there are pragmatic challenges in arranging for this to be done at centers remote to our own where our study staff are not available.Currently, only a minority of patients are treated outside of Mayo Rochester and Yale University sites, so we do not anticipate this will substantially impact any comparisons of data.
Under PRO -there seem to be so many PRO questions-how would the authors consider or prevent patient questionnaire fatigue?This is further exacerbated by weekly questions for the first 2 months.
Why not just keep it on a monthly basis rather than weekly for the first 2 months?Again, I understand that you have now collected this data for more than half of your sample size.
Response: As opposed to an interventional clinical trial, when PRO assessments are integrated with other requirements that can place burden on patients such as research blood draws, research imaging and research clinic visits, in the In4M study, the assessments are limited to the PROs and the two 6-minute walk tests (in addition to passively collected wearable data) only.Patient advocates were involved in the design of the study and approved the number of PRO questions at each time point.Participants are specifically consented with the PRO assessment schedule in mind, and additionally they are compensated for their time in filling out questionnaires.The questionnaires intentionally vary in length to ask only the questions that were felt to be necessary at any given timepoint, and most of the weekly questionnaires are shorter.FDA Guidance includes a schedule of assessments that includes weekly PROs even in large phase 3 trials, to characterize adverse events and impacts on function that can be worse in the first couple of months on a new cancer therapy.Additionally, with the Hugo platform, participants are able to complete surveys at home, in office waiting rooms, or anywhere that is convenient, at a time that is convenient to them.Of the patients enrolled on the study thus far, the completion rates are excellent which suggests burden is manageable.However, understanding survey fatigue is an important component of the study and is assessed on the exit survey (now included in Appendix 2, question 6).
Under wearable data -were there any instructions to the patients about planned exercise or physical activity -if there were, what was it?If not, please elaborate on this in the manuscript.
Response: There was no specific instruction to patients about planned exercise or physical activity.
The focus of the study was to characterize patients' physical function as it is on cancer therapy, not to provide an exercise program or modify the physical activity.We have added the following sentence to the first paragraph of the methods: "The focus of this non-interventional study is to characterize patients' physical function trajectories on cancer therapy without any intervention, so no exercise program or activity guidance are given." Please elaborate on the exit questionnaire.
Response: The exit questionnaire was designed specifically for this study, to assess patients' perceptions of their own physical function, the surveys completed during the study, and the wearable device.A full copy of the exit questionnaire is now provided in Appendix 2. A paragraph clarifying this has also been added to the Methods section.
6MWT -why not measure at the end of the study at M9 too?What was the reason not to do this and only at 2-time points?
Response: We agree with the reviewer that it would have been ideal to measure the 6MWT at the end of study, as well as at other time points throughout treatment.Nonetheless, there are pragmatic clinical challenges in arranging for this to be done.When patients come for a treatment day, they have lab tests drawn, see their care providers, and then typically proceed directly to the chemotherapy unit for treatment on the same day, with little break in between.It was felt it would be burdensome to require participants to meet with the study coordinators post chemotherapy, and most patients are not physically present other than on the day of treatment to complete this in-person assessment.
Reviewer: 2 Thanks for the opportunity to review this manuscript titled 'Integrating 4 Measures to Evaluate Physical Function in Patients with Cancer (In4M): Protocol for a prospective study' for publication in BMJ Open.The manuscript outlines the protocol for a study currently recruiting to characterise longitudinal measurement characteristics (variability, sensitivity and meaningful changes) of a range of different physical function tests in people with breast cancer or lymphoma receiving chemotherapy.
The study will also report on physical function relationships to clinical outcomes and feasibility of data collection.The manuscript will make an important contribution to scientific knowledge on this topic Introduction Page 11 lines 32-41would be more informative if the strength of the correlations mentioned in this section were presented (e.g., r values or 'fair', 'good' etc as defined by Cohen) Response: We have added a reference to Cohen's 1988 book for all effect size statements.We have also added a delineation of small, moderate, and large effect sizes for correlation.
Brief background regarding the development of 'Hugo Health' would help the reader to understand how the measurements are truly 'patient-centred'.For example were patients or carers involved in its design?Readers can then refer to the previous publications for additional information.
Response: Thank you for your comment.The data aggregation platform, Hugo Health, is considered 'patient-centered' due to its ability to consolidate data from 'patient-centered' sources, such as electronic health records and patient surveys.Patients can complete surveys on their mobile devices or computer on their own time which is generally felt more patient-centered than in-clinic paper surveys.Additionally, by gathering electronic health record data to identify information on parameters such as hospitalizations or emergency visits, patients do not have to be contacted directly, which thus reduces participant burden.We have included the website reference to the Hugo Health platform for further details (reference #47, Dhruva SS et al, NPH Digit Med 2020;3:60.).

PerfO
Page 15 line 24the 6MWT is being performed once, yet the guidelines from the ATS/ERS state that 2 tests should be performed to account for any potential learning effects (Holland et al, ERJ, 2014).
Changes in performance which are measured between the two timepoints could be a result of learning effects rather than true change in performance and this should be stated as a limitation to the study methods.
Response: The 6MWT is being performed twice, once at baseline and again at 3 months (page 13) in the majority of patients.In a small minority of patients who are not treated at Mayo Clinic Rochester, Yale University or Yale affiliated community sites, we are unable to perform the 2nd assessment of the 6MWT.At current status, this is a very small group of patients on the study and we anticipate most participants will have 2 assessments for robust comparison.The reviewer's point about learning effects rather than true change in performance is a valid limitation.We have included this in the Methods, paragraph 4.

Wearable data
Wear of devices for 9 months day and night, with data uploads every 3 days, is asking a lot of participants, particularly when most clinical trials have a 7-10 day wear period at each assessment timepoint and include data so long as 4 days of 8 hours data/day is available.Given data collection is continuous over the 9 months how will missing data be reported (e.g., will it be clear if participants have met minimum data requirements as outlined above)?